Process for the preparation of dinaposoline

ABSTRACT

The present invention relates to a novel process for the preparation of compounds of the formulawherein R&lt;1&gt;, R&lt;2&gt;, R&lt;4&gt;, R&lt;5&gt;, R&lt;6 &gt;and A are as defined herein, and to certain derivations of Formula IX which are useful for the treatment of movement disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. national counterpart application ofinternational application serial No. PCT/US01/25265 filed Aug. 10, 2001,which claims priority to U.S. provisional application serial No.60/224,968 filed Aug. 11, 2000.

FIELD OF THE INVENTION

The present invention provides a process for the preparation ofdinapsoline and certain derivatives thereof which are useful as dopaminereceptor agonists in the treatment of movement disorders.

BACKGROUND OF THE INVENTION

Dopamine has been implicated in numerous neurological disorders. It isgenerally recognized that either excessive or insufficient functionaldopaminergic activity in the central and/or peripheral nervous systemmay cause hypertension, narcolepsy, and other behavioral, neurological,physiological, and movement disorders including Parkinson's disease, achronic, progressive disease characterized by an inability to controlthe voluntary motor system.

A number of ligands for the treatment of dopamine-related dysfunction ofthe central and peripheral nervous system are described in InternationalPatent No. WO 97/06799, published Feb. 27, 1997, having the generaltetrahydro-1H-naph[1,2,3-de]isoquinoline chemical structure describedbelow.

In particular, the international application specifically describes thesynthesis and use of(±)-8,9-dihydroxy-2,3,7,11b-tetrahydro-1H-naphtho[1,2,3-de]isoquinolinedenominated as “dinapsoline” in the description. The synthesis ofdinapsoline is depicted generally in FIGS. 1 and 2 as well as in theexperimental section. Further description of the synthesis andpharmacological evaluation of dinapsoline is described by D. Ghosh, etal. in J. Med. Chem., Vol. 39, pp. 549-555 (1996).

Although the prior art process works on a small scale, the overallprocess is a long synthesis which involves as many as 14 steps tocomplete, including protection and deprotection schemes. The cyclizationstep near the end of the synthesis was found to be problematic and theyield not reproducible, if there is any product at all. Thus, there is aneed for a simple, convenient, economical and scale-up for thepreparation of dinapsoline and derivatives thereof. The presentinventors have found a suitable process that avoids the problematiccyclization step which uses an isoquinoline system and a highlyregloselective carbon-carbon bond forming technique to establish theentire tetracyclic framework in a few simple steps.

SUMMARY OF THE INVENTION

The present invention relates to fused isoquinoline compounds of theformula

wherein R¹, R², R⁴, R⁵, R⁶ and A are as defined herein which are usefulfor the treatment of movement disorders. More specifically, theinvention relates to a process for their preparation.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel process for the preparation ofdinapsoline and derivatives thereof which are useful for the treatmentof movement disorders, and have the formula

wherein R¹ and R² each are independently hydrogen or ahydroxy-protecting group; or R¹ and R² may be joined together to form—(CH₂)_(n)—; n is 1 to 3; A is CH₂, CHOR¹ or C═O; and R⁴, R⁵ and R⁶ eachare independently hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, hydroxy or halogen.The novel and improved process is illustrated in Reaction Scheme 4.

The present invention also provides certain dinapsoline derivatives ofFormula IX which are useful for the treatment of movement disorders.

The term “C₁₋₄ alkyl” as used herein and in the claims (unless thecontext indicates otherwise) means straight or branched chain alkylgroups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl andt-butyl. The term “C₁₋₄ alkoxy” as used herein and in the claims meansstraight or branched chain alkoxy groups such as methoxy, ethoxy,propoxy and butoxy. Preferably, these groups contain from 1 to 2 carbonatoms. Unless otherwise specified, the term “halogen” as used herein andin the claims is intended to include bromine, chlorine, iodine andfluorine while the term “halide” is intended to include bromine,chloride and iodide anion. The term “A” as used herein and in the claimsis independently selected from a methylene (—CH₂—) group, a hydroxy orhydroxy-protected methylene (—CHOR¹) group or a carbonyl (C═O) group.

The term “hydroxy-protecting group” refers to those groups well known tothose skilled in the art which can be employed in the present inventionto block or protect the hydroxyl group. Preferably, said groups can beremoved, if desired, by methods which do not result in any appreciabledestruction of the remaining portion of the molecule, for example, bychemical or enzymatic hydrolysis, treatment with chemical reducingagents under mild conditions, irradiation with ultraviolet light orcatalytic hydrogenation.

Suitable hydroxy-protecting groups include acyl groups such as acetyl,propionyl, butyryl, chloroacetyl, dichloroacetyl and trichloroacetyl,phenoxycarbonyl, benzyloxycarbonyl, benzhydryloxycarbonyl,trityloxycarbonyl, p-nitro-benzyloxycarbonyl and2,2,2-trichloroethoxy-carbonyl; aroyl groups such as benzoyl andsubstituted benzoyl, for example, methoxybenzoyl, nitrobenzoyl,methylbenzoyl and the like; alkyl groups such as methoxymethyl,benzyloxymethyl, alkyl; aralkyl groups such as benzyl, benzhydryl,trityl or p-nitrobenzyl; or triorganosilyl groups such astri(C₁-C₆)alkylsilyl (e.g. trimethylsilyl, triethylsilyl,triisopropylsilyl, isopropyidimethylsilyl, t-butyidimethylsilyl,methyldlisopropyisilyl or methyldi-t-butylsilyl), triarylsilyl (e.g.triphenyl-silyl, tri-p-xylsilyl) or triaralkylsilyl (e.g.tribenzysilyl). Examples of these and other suitable hydroxy-protectinggroups and methods for their formation and removal are known in the art,e.g. see Protective Groups in Organic Synthesis, T. W. Greene, JohnWiley & Sons, New York, 1991, Chapter 2, and references therein.

Preferred hydroxy-protecting groups are acyl groups such as acetyl,propionyl and chloroacetyl; aroyl groups such as benzoyl and substitutedbenzoyl and aryl groups such as benzyl and substituted benzyl. Mostpreferably, the hydroxy-protecting group is achieved when R¹ and R² arejoined together to form a methylene (—CH₂—) group.

It should be appreciated by those skilled in the art that the finaldeblocking step will naturally vary depending on the protecting groupspresent in substituents R¹ and R². The deblocking step such asillustrated in Reaction Scheme 4, step (g), to produce compounds ofFormula IX wherein R1 and R² are hydrogen is accomplished byconventional procedures such as hydrolysis, chemical reduction,hydrogenation and the like, and includes the method illustrated for theremoval of the hydroxy-protecting group wherein R¹ and R² are joinedtogether to form —CH₂—.

The compounds of Formula IX may be prepared by various procedures suchas those illustrated herein in the examples, in the Reaction Schemes andvariations thereof which would be evident to those skilled in the art.The fused isoquinolines of Formula IX may advantageously be prepared byreduction methods from benzo benzoisoquinoline compounds of Formula VIIfollowed by removal of the hydroxy-protecting groups as illustrated inReaction Scheme 4. The various benzo benzoisoquinolines of Formula VIImay advantageously be prepared using free radical carbon-carbon bondformation from aryl isoquinolines of Formula VI as illustrated inReaction Scheme 3 while the aryl isoquinolines of Formula V may beprepared from isoquinolines of Formula I and appropriately substitutedphenyl derivatives by the method illustrated in Reaction Scheme I andthe alternative method illustrated in Reaction Scheme 2.

As illustrated in Reaction 1, the compounds of Formula V may be preparedfrom substituted or unsubstituted isoquinolines of the Formula I whichare generally known to undergo electrophilic substitution preferentiallyat the 5-position to give 5-bromo-isoquinolines of the Formula II. Thebromination reaction (a) can be done in neat form and in the presence ofa Lewis Acid catalyst such as anhydrous aluminum chloride, oralternatively, the bromination can be carried out in an inert organicsolvent such as methylene chloride. In both cases, the overall yieldsare comparable to each other, and preferably, the bromination is carriedout in neat form since it avoids the additional solvent evaporationstep. The 5-bromo-isoquinoline compound of Formula II can betrans-metallated to the corresponding 5-lithio-isoquinoline usingn-butyl lithium in a suitable inert organic solvent such as THF and thereaction is preferably carried out at a temperature below −50 to −80° C.This versatile 5-lithio-isoquinoline can be alkylated, acylated into avariety of 5-substituted isoquinolines. The addition of DMF to said5-lithio-isoquinoline followed by warming to room temperature andneutralization with an equivalent amount of mineral acid, this5-lithio-isoquinoline produced the 5-formyl-isoquinoline of Formula IIIin excellent yields. Using a recently published procedure described byR. Mattson, et al., in ACS Organic Division, 1998, Boston Abstract No.059, the aldehyde of Formula ill may advantageously be reacted with the4-bromo-3-lithio-1,2-(methylenedioxy)benzene derived from thecorresponding hydrocarbon precursor of Formula IV to furnish the desiredbenzhydrol of Formula V, in crystalline form.

Reagents: (a) Br₂/AlCl₃/neat; (b) LDA then IVa; (c) n-BuLi then DMF

The desired compounds of Formula V can alternatively be prepared by asimilar but different route which differs in the formulation step asillustrated in Reaction Scheme 2.

The formulation reaction in converting the compound of Formula II to thecompound of Formula III which is described above and shown in ReactionScheme I can be carried out on4-bromo-3-ithio-1,2-(methylenedioxy)benzene to give the corresponding2-bromo-5,6-(methylenedioxy)benzaldehyde, of Formula IVa. The aldehydeof Formula IVa is then readily reacted with the lithiated5-bromo-isoquinoline to produce the identical benzhydrol of Formula V.These complementary and convergent processes are provided to accommodatedifferent pairs of isoquinolines and4-bromo-1,2-(methylenedioxy)benzenes of the present invention.

Reagents: (a) MnO₂/benzene; (b) n-Bu₃SnH/AIBN; (d) Et₃SiH/TFA; (e)n-Bu₃SnH/AIBN

The benzhydrols of Formula V can readily be converted to the arylisoquinolines of Formulas VIa; VIb and VIc which are usefulintermediates for the preparation of dinapsoline and derivativesthereof. It should be appreciated by those skilled in the art that thealcohol of Formula V can readily be oxidized to the corresponding ketoneof Formula VIa in a conventional manner with an oxidizing agent such asmagapese dioxide. The alcohol of Formula V can readily be protected witha hydroxy-protecting group to afford the compound of Formula Vic whilereduction provides the compound of Formula VIb.

The cyclization of the compound of Formulas VIa, VIb and VIc to thecorresponding compounds of Formulas VIa, VIIb and VIIc can be initiatedby a variety of reaction conditions well-known to those skilled in theart. However, it was found that the best results were achieved by freeradical initiated carbon-carbon bond formation since this method was theleast sensitive to the electronic environment of the selected precursor.The carbon-carbon bond reaction is preferably carried out with ahydrogen radical source such as trialkyltin hydride, triaryltin hydride,trialkylsilane, triarylsilane or the like and a radical initiator suchas 2,2′-azobisisobutylronitrile, sunlight, controlled potential cathodic(Pt) or the like in the presence of a proton source such as a mineralacid, for example, sulfuric acid and hydrochloric acid or an organicacid, for example, acetic acid, trifluoroacetic acid andp-toluenesulfonic acid. In the conversion of compound of Formula VIb tothe cyclized compound of Formula VIIb, it is advantageous and preferredto use tributyltin hydride with a variety of well-known initiators andspecifically, 2,2′-azobisisobutylronitrile in the presence of aceticacid.

Reagents: (f) NaBH₃CN in HCl/THF; (g) BBr₃S/CH₂Cl₂; (h) Pd/C in xylenes

Once cyclized, the intermediates of Formulas VIIa, VIIb and VIIc areuseful as starting materials for various, derivatives which differ onlyat one position in the definition of substituent A as illustrated inReaction Scheme 4. The compound of Formula VIIb is selectively reducedat the nitrogen bearing heterocyclic ring to give the correspondingtetrahydroisoquinoline of Formula VIIb, the direct precursor of thedinapsoline derivatives of Formula IXb. The selective ring reduction maybe carried out by a number of different reduction methods such as sodiumcyanoborohydride in an acidic medium in THF, hydride reducing agentssuch as L-Selectride® or Superhydride® and preferably, catalytichydrogenation under elevated pressure may be employed. It should beappreciated by those skilled in the art that alternatively, the reverseof said ring reduction can be carried out by using palladium catalyzeddehydrogenation at elevated temperature in an organic solvent such asboiling xylenes. Conversion of the protected compound of Formula VIIIbto the diol of Formula IXb may be accomplished by using boron tribromidein methylene chloride at low temperatures such as −60 to −80° C. and thefinal product may be isolated in the form of a hydrobromide salt, whilethe corresponding hydrochloride salt may advantageously be prepared byusing boron trichloride instead. If it is desired to prepare thecompound of Formula IXb wherein R is C₁₋₄ alkyl, then it is advantageousto alkylate the compound of Formula VIIb using conventional methodsbefore the protecting groups are removed to afford the desired diol ofFormula IXb.

When it is desired to prepare the corresponding compounds of Formula IXwherein A is a hydroxy group (IXc) or a carbonyl group (IXa) as furtherillustrated in Reaction Scheme 4, the approximate precursor of FormulaVIIIa maybe converted to the desired compound of Formula IXa while thesuitably protected compound of Formula VIIIc may advantageously bedeprotected to provide the alcohol compounds of Formula IXc. It shouldbe appreciated by those skilled in the art, the conversion of andmodification of the A substituent in the compound of Formula IX may beconverted readily from one compound to the other by well-knownconventional procedures as illustrated in Reaction Scheme 4 for thecompounds of Formulas IXa, IXb and IXc.

In a preferred embodiment of the invention the compounds of Formula VIhave the formula

wherein R¹ and R² each are independently hydrogen or ahydroxy-protecting group; or R¹ and R² may be joined together to form—(CH₂)_(n)—; n is 1 to 3, R³ is chloro, bromo or iodo; A is CH₂, CHOR¹or C═O; and R⁴, R⁵ and R⁶ each are independently hydrogen, C₁₋₄alkyl,C₁₋₄alkoxy, hydroxy or halogen. It is most preferred that R¹ and R² arejoined together to form —(CH₂)_(n)— wherein n is 1, R³ is bromo, A isCH₂ and R⁴, R⁵ and R⁸ are hydrogen.

In another preferred embodiment of the invention the compounds ofFormula VII have the formula

wherein R¹ and R² each are hydrogen or a hydroxy-protecting group; or R¹and R² may be joined together to form —(CH₂)_(n)—; A is CH₂, CHOR¹ orC═O; n is 1 to 3; and R⁴, R⁵ and R⁶ each are independently hydrogen,C₁₋₄alkyl, C₁₋₄alkoxy, hydroxy or halogen. It is most preferred that R¹and R² are joined together to form —(CH₂)_(n)— wherein n is 1, A is CH₂and R⁴, R⁵ and R⁶ are hydrogen.

In still another preferred embodiment of the invention the compounds ofFormula IX have the formula

wherein R¹ and R² each are hydrogen or a hydroxy-protecting group; or R¹and R² may be joined together to form —(CH₂)_(n)—; n is 1 to 3; A isCHOR¹ or C═O; R is hydrogen or C₁₋₄alkyl; and R⁴, R⁵ and R⁶ each areindependently hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, hydroxy or halogen. It ismost preferred that R¹ and R² are joined together to form —(CH₂)_(n)—wherein n is 1, A is CH₂ and R, R⁴, R⁵ and R⁶ are hydrogen.

In another aspect, this invention provides a process for the preparationof a compound of Formula IX

wherein R¹ and R² each are hydrogen; A is CH₂, CHOH or C═O; R ishydrogen or C₁₋₄alkyl; and R⁴, R⁵ and R⁶ each are independentlyhydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, hydroxy or halogen, comprising thesteps of (a) reducing a compound of the formula

wherein R¹ and R² each are a hydroxy-protecting group; or R¹ and R² maybe joined together to form —(CH₂)_(n)— in which n is 1 to 3 and R⁴, R⁵and R⁶ and A are as defined above; with a reducing agent and (b)deprotectng the resulting reduced product to produce the compound ofFormula IX wherein R¹ and R² are hydrogen and (c) optionally, alkylatingthe product of step (a) or (b) to produce a compound of Formula IXwherein R is C₁₋₄alkyl; Preferably, in the process of the invention R¹form —(CH₂)_(n)— wherein n is 1, R³ is bromo, A is CH₂ and R⁴, R⁵ and R⁶are hydrogen and R² are joined together to form —(CH₂)—, A is CH₂ and R,R⁴, R⁵ and R⁶ are hydrogen.

Binding to Dopamine Receptors

Dopamine produces biological responses through stimulation of itsreceptors on cell membranes. The affinity for D₁ and D₂ receptors werecarried out in rat stratum using the in vitro binding assay adapted fromC. P. Manik, P. B. Molinoff and P. McGonigle in J. of Neurochemistry.Vol. 51, pp. 391-397 (1988) and K. D. Burnis, et al., inNeuropsychoopharmacology. Vol. 12, pp. 335-345 (1995). In addition,membranes prepared from HEK-293 cells that express transfected humanD_(2L) receptors, sites labeled by the D₂ receptor agonist[¹²⁵I]-7-OH-PIPAT were used and the results show that the compounds ofthe present invention are active in these tests.

In another embodiment, this invention includes pharmaceuticalcompositions comprising at least one compound of Formula IX incombination with a pharmaceutical adjuvant, carrier or diluent.

In still another embodiment, this invention relates to a method for thetreatment of movement disorders a mammal in need thereof, whichcomprises administering to said mammal a therapeutically effectiveamount of a compound of Formula IX or a nontoxic pharmaceuticallyacceptable salt, solvate or hydrate thereof.

In yet another embodiment this invention relates to a method fortreating Parkinson's disease in a mammal in need thereof, whichcomprises administering to said mammal a therapeutically effectiveamount of a compound of Formula IX or a non-toxic pharmaceuticallyacceptable salt, solvate or hydrate thereof.

For therapeutic use, the pharmacologically active compounds of FormulaIX will normally be administered as a pharmaceutical compositioncomprising as the (or an) essential active ingredient at least one suchcompound in association with a solid or liquid pharmaceuticallyacceptable carrier and, optionally, with pharmaceutically acceptableadjuvants and excipients employing standard and conventional techniques.

The pharmaceutical compositions include suitable dosage forms for oral,parenteral (including subcutaneous, intramuscular, intradermal andintravenous) bronchial or nasal administration. Thus, if a solid carrieris used, the preparation may be tableted, placed in a hard gelatincapsule in powder or pellet form, or in the form of a troche or lozenge.The solid carrier may contain conventional excipients such as bindingagents, fillers, tableting lubricants, disintegrants, wetting agents andthe like. The tablet may, if desired, be film coated by conventionaltechniques. If a liquid carrier is employed, the preparation may be inthe form of a syrup, emulsion, soft gelatin capsule, sterile vehicle forinjection, an aqueous or non-aqueous liquid suspension, or may be a dryproduct for reconstitution with water or other suitable vehicle beforeuse. Liquid preparations may contain conventional additives such assuspending agents, emulsifying agents, wetting agents, non-aqueousvehicle (including edible oils), preservatives, as well as flavoringand/or coloring agents. For parenteral administration, a vehiclenormally will comprise sterile water, at least in large part, althoughsaline solutions, glucose solutions and like may be utilized. Injectablesuspensions also may be used, in which case conventional suspendingagents may be employed. Conventional preservatives, buffering agents andthe like also may be added to the parenteral dosage forms. Particularlyuseful is the administration of a compound of Formula IX directly inparenteral formulations. The pharmaceutical compositions are prepared byconventional techniques appropriate to the desired preparationcontaining appropriate amounts of the active ingredient, that is, thecompound according to the invention. See, for example, Remington'sPharmaceutical Sciences. Mack Publishing Company, Easton, Pa., 17thedition, 1985.

The dosage of the compounds of Formula IX to achieve a therapeuticeffect will depend not only on such factors as the age, weight and sexof the patient and mode of administration, but also on the degree ofpotassium channel activating activity desired and the potency of theparticular compound being utilized for the particular disorder ofdisease concerned. It is also contemplated that the treatment and dosageof the particular compound may be administered in unit dosage form andthat the unit dosage form would be adjusted accordingly by one skilledin the art to reflect the relative level of activity. The decision as tothe particular dosage to be employed (and the number of times to beadministered per day) is within the discretion of the physician, and maybe varied by titration of the dosage to the particular circumstances ofthis invention to produce the desired therapeutic effect.

A suitable dose of a compound of Formula IX or pharmaceuticalcomposition thereof for a mammal, including man, suffering from, orlikely to suffer from any condition as described herein is an amount ofactive ingredient from about 0.1 μg/kg to 100 mg/kg, body weight. Forparenteral administration, the dose may be in the range of 1 μg/kg to 10mg/kg body weight for intravenous administration. The active ingredientwill preferably be administered in equal doses from one to four times aday. However, usually a small dosage is administered, and the dosage isgradually increased until the optimal dosage for the host undertreatment is determined.

However, it will be understood that the amount of the compound actuallyadministered will be determined by a physician, in the light of therelevant circumstances including the condition to be treated, the choiceof compound of be administered, the chosen route of administration, theage, weight, and response of the individual patient, and the severity ofthe patient's symptoms.

The following examples are given by way of illustration and are not tobe construed as limiting the invention in any way inasmuch as manyvariations of the invention are possible within the invention.

DESCRIPTION OF SPECIFIC EMBODIMENTS

All new compounds reported displayed spectral characteristics (IR, MS,¹H and ¹³C NMR) which were consistent with their assigned structures.NMR's were run in the indicated solvent [deuterochloroform (CDCl₃) orperdeuterodimethylsulfoxide (DMSO-d₆)] at 300 MHz using a Bruker ACP 300spectrometer. Data are reported as follows: chemical shift (δ) in PPMdownfield from calculated tetramethylsilane (TMS); multiplicity(s=singlet, d=cdoublet, t=triplet, q=quartet, p=pentuplet, andbr=broadened), integration and coupling constant (given in Hz). Meltingpoints were obtained using a Thomas Hoover capillary apparatus and areuncorrected.

EXAMPLE 1 5-Bromoisoquinoline

The apparatus consisted of a 500 mL three-necked flask equipped with acondenser, dropping funnel and a stirrer terminating in a stiff,crescent-shaped Teflon polytetrafluroethylene paddle. To isoquinoline(57.6 g, 447 mmol) in the flask was added AlCl₃ (123 g, 920 mmol). Themixture was heated to 75-85° C. Bromine (48.0 g, 300 mmol) was addedusing a dropping funnel over a period of 4 hours. The resulting mixturewas stirred for one hour at 75° C. The almost black mixture was pouredinto a vigorously hand-stirred cracked ice. The cold mixture was treatedwith sodium hydroxide solution (10N) to dissolve all the aluminum saltsas sodium aluminate and the oily layer was extracted with ether. Afterbeing dried with Na₂SO₄ and concentrated, the ether extract wasdistilled at about 0.3 mm. A white solid (16.3 g, 78 mmol) from afraction of about 1.25° C. was obtained (26% yield). The product wasfurther purified by recrystallization (pentane or hexanes): mp 80-81°C.;

¹H NMR (DMSO-d₆) δ 9.34 (s, 1H), 8.63 (d, 1H, J=9.0 Hz), 8.17 (d, 1H,J=7.5 Hz), 8.11 (d, 1H, J=6.6 Hz), 7.90 (d, 1K, J=6.0 Hz, 7.60 (t, 1H,J=7.5 Hz); ¹³C NMR (DMSO-d₆) δ 153.0, 144.7, 134.3, 134.0, 129.3, 128.5,128.0, 120.3, and 118.6. Anal. Calcd. for C₉H₆BrN: C, 51.96; H, 2.91; N,6.73. Found: C, 51.82; H, 2.91, N, 6.64.

EXAMPLE 2 5-Isoquinolinecarboxaldehyde

To a solution of n-butyllithium (19.3 mL of 2.5M in hexanes, 48 mmol) ina mixture of ether (80 mL) and THF (80 mL) at −78° C. was added dropwisea solution of bromoisoquinoline (5.0 g, 24 mmol) in THF (10 mL). Thereaction mixture was stirred at −78° C. under argon for 30 minutes.Following the general procedures described by Pearson, et al., in J.Heterocycl. Chem., Vol. 6 (2), pp. 243-245 (199), a solution of DMF(3.30 g, 45 mmol) in THF (10 mL) was cooled to −78° C. and quickly addedto the isoquinolyllithium solution. The mixture was stirred at −78° C.for 15 minute. Ethanol (20 mL) was added followed by saturated NH₄Clsolution. The resulting suspension was warmed to room temperature. Theorganic layer, combined with the ether extraction layer, was dried overNa₂SO₄. A pale yellow solid (2.4 g, 15 mmol, 64% yield) was obtainedfrom chromatography (SiO₂ Type-H, 50% EtOAc in hexanes) andrecrystallization (ethanol): mp 114-116° C.;

¹³H NMR (DMSO-d₆) δ 10.40 (s, 1H), 9.44 (s, 1H), 8.85 (d, 1H, J=6.0 Hz,8.69 (d, 1H, J=6.0 Hz, 8.45 (m, 2H), 7.90 (t, 1H, J=7.2 Hz); ¹³C NMR(DMSO-d₆)) δ 194.23, 153.5, 146.2, 140.2, 135.2, 132.6, 130.2, 128.6,127.5, and 117.2. Anal. Calcd. for C₁₀H₇NO.0.05H₂O: C, 75.99; H, 4.53;N, 8.86. Found: C, 75.98; H, 4.66, N, 8.68.

EXAMPLE 3 4-Bromo-1,2-(methylenedioxy)-3-benzaldehyde

To a solution of 4-bromo-1,2-(methylenedioxy)benzene (24.9 mmol) in THF(52 mL) at −78° C., lithium diisopropylamide in 1.5M in cyclohexane(27.4 mmol) was slowly added and the resulting solution was stirred for15 minutes. DMF (4.15 mL) was then added dropwise and the reactionsolution was allowed to warm at room temperature for 1 hour. Thesolution was washed with saturated NH₄Cl and the organic layer wasconcentrated and dried under vacuo. The yellow solid product wasrecrystallized using isopropyl acetate to afford the title compound asyellow needles (69% yield). mp 158-159° C.;

¹H NMR (CDCl₃) δ 10.29 (s, 1H), 7.08 (d, 1H, J=8.25 Hz, 6.83 (d, 1HJ=8.22 Hz), 6.17 (s, 2H); ¹³C NMR CDCl₃) δ 190.8, 149.8, 149.1, 126.5,117.7, 115.9, 113.9, 103.8. Anal. Calcd. for C₈H₅BrO₃: C, 41.95; H,2.20; Br, 34.89 Found: C, 41.91; H, 2.09; Br, 34.56.

EXAMPLE 4 α-(5-Bromo-1,3-benzodioxal-4-yl)-5-isoquinolinemethanol

To a solution of 4-bromo-1,2-(methylendioxy)benzene (3.01 g, 15 mmol) inTHF (20 mL) at −78° C. was added dropwise lithium diisopropylamide (10.6mL of 1.5M in cyclohexane, 16 mmol). The reaction mixture was stirred at−78° C. under argon for 20 minutes. A brown solution was formed. Asolution of 5-isoquinolinecarboxaldehyde (1.90 g, 12 mmol) in THF (4 mL)was added dropwise. The resulting mixture was stirred at −78° C. for 10minutes and warmed to room temperature. Stirring was continued for 30minutes at room temperature, and then the mixture was quenched withsaturated NH4Cl solution. The product was extracted with EtOAc and thesolvent was removed under reduced pressure. Chromatography (SiO2 Type-H,35% EtOAc in Hexanes) of the residue yielded the title compound as ayellow solid (2.8 g, 7.8 mmol, 65% yield): mp 173-175° C.;

¹H NMR (DMSO-d₆) δ 9.32 (s, 1H), 8.47 (d, 1H, J=6.0 Hz), 8.05 (d, 1H,J=8.1 Hz), 7.96 (d, 1H, J=7.2 Hz), 7.76 (d, 1H, J=6.0 Hz), 7.66 (t, 1H,J=7.8 Hz), 7.14 (d, 1H, J=8.1 Hz), 6.84 (d, 1H, J=8.1 Hz), 6.58 (d, 1H,J=8.1 Hz), 6.28 (d, 1H, J=5.4 Hz), 5.95 (s, 1H), 5.80 (s, 1H); ¹³C NMR(DMSO-D₆) δ 153.1, 147.6, 147.0, 142.9, 136.9, 132.7, 128.9, 128.3,127.3, 126.7, 125.6, 124.4, 116.3, 114.0, 109.3, 101.6, and 69.0. Anal.Calcd. for C₁₇H₁₂BrNO₃: C, 57.01; H, 3.38; N, 3.91. Found: C, 57.04; H,3.51, N, 3.89.

EXAMPLE 5 α-(5-Bromo-1,3-benzodioxol-4-yl)-5-isoquinolinemethanol

To a solution of 5-bromoisoquinoline (0.50 g, 2.4 mmol) in ether (8 mL)at −78° C. was added dropwise t-butyllithium (3.6 mL of 1.7M in pentane,6.0 mmol) under argon. The mixture was stirred at −78° C. under argonfor 30 minutes then continued for 15 minutes with the flask right abovethe dry-ice acetone bath. 4-Bromo-1,2-(methylenedioxy)-3-benzaldehyde(0.524 g, 2.4 mmol) was added in one portion at −78° C. under argon. Themixture was stirred at −78° C. for five minutes and then was warmed toroom temperature using a water bath. Stirring was continued for 20minutes at room temperature and then the mixture was quenched withsaturated NH₄Cl, extracted with EtOAc and dried over Na₂SO₄.Chromotography (SiO₂, 35% EtOAc in hexanes) yielded the title compoundas, a yellow solid (0.18 g, 0.50 mmol, 21% yield) which is identical tothe compound of Example 4.

EXAMPLE 6 5-[(5-Bromo-1,3-benzodioxol-4yl)methyl]isoquinoline

To a solution of secondary alcoholα-(5-bromo-1,3-benzodioxol-4-yl)-5-isoquinolinemethanol (8.37 mmol) intrifluoroacetic acid (100 mL), triethylsilane (83.7 mmol) was added andthe resulting solution was refluxed for an hour at 70-75° C. and stirredovernight at room temperature. The solvent was removed under vacuo andthe residue was dissolved in ethyl acetate washed with saturated NH₄Cldried over Na₂SO₄, filtered and concentrated. Purification was performedby column chromatography to afford the trifluoroacetate salt of thetitle compound as a white crystalline solid (67% yield): mp 138-140° C.;

¹H NMR (CDCl₃) δ 9.64 (s, 1H), 8.63 (d, 1H, J=6.59 Hz), 8.45 (d, 1H,J=6.62 Hz), 8.14 (d, 1H, J=8.22 Hz), 7.77 (t, 1H, J=7.39 Hz), 7.64 (d,1H, J=7.29 Hz, 7.13 (d, 1H, J=8.33 Hz), 6.71 (d, 1H, J=8.31 Hz) 5.94 (s,2H), 4.53 (s, 2H); ¹³C NMR (CDCl₃) δ 147.8, 147.7, 147.1, 137.2, 135.1,134.7, 133.4, 130.3, 128.6, 128.3, 125.9, 120.7, 119.4, 116.3, 109.1,101.9 and 31.7. Anal. Calcd. for C₁₇H₁₂BrNO₂.C₂HF₃O₂: C, 50.02; H, 2.87;Br, 17.51; N, 3.07. Found: C, 49.91; H, 3.02; Br, 17.95; N, 3.04.

EXAMPLE 7 12H-Benzo[d,e][1,31]benzodioxol[4,5-h]isoquinoline

Method A:

A solution of 5-[(5-bromo-1,3-benzodioxol-4-yl)methyl]-isoquinoline(0.357 g, 1.0 mmol) and 2,2′-azobisisobutylronitrile (0.064 g, 0.39mmol) in benzene (10 mL) was cooled to −78° C., degassed four times withN₂ and then heated to 80° C. under argon. A solution of tributyltinhydride (1.14 g, 3.9 mmol) in 10 mL of degassed benzene was added in twohours. TFA (0.185 g, 1.6 mmol) was added in four equal portions (¼ eachhalf hour). The reaction mixture was stirred at 80° C. under argon forsix hours after addition of TFA. Additional tributyltin hydride (0.228g, 0.80 mmol) was added dropwise. The stirring continued overnight (16hours). Another 2,2′-azobisisobutylronitrile (0.064 g, 0.39 mmol) andTFA (0.093 g, 0.80 mmol) were added in one portion. A solution oftributyltin hydride (1.14 g, 3.9 mmol) in 10 mL of degassed benzene wasalso added in two hours. More TFA (0.185 g, 1.6 mmol) was added in fourequal portions (¼ each half hour). The stirring continued for anothersix hours and tributyltin hydride (0.456 g, 1.6 mmol) was addeddropwise. The reaction mixture was stirred overnight (16 hours). Thesolvent was removed under reduced pressure. Pentane (100 mL) was addedto residue and resulting mixture was cooled to −78° C. A brown gum wasformed and filtered. The filtrate was extracted with MeCN. The MeCNlayer was combined with the brown gum. The crude product fromevaporation of MeCN was purified by chromatography (SiO₂ Type-H, 15%EtOAc in hexanes). The isolated compound was dissolved in CH₂Cl₂ andextracted with HCl (1N). The aqueous layer was basified to pH˜10 using10N of NaOH solution and reextracted with CH₂Cl₂. The organic layer wasdried over Na₂SO₄. Evaporation of solvent yielded the title compound asan orange solid (0.068 g, 0.26 mmol, 25% yield): mp 194-197° C.;

¹H NMR (DMSO-d₆) δ 9.12 (s, 1H), 9.06 (s, 1H), 7.93 (d, 1H, J=6.9 Hz),7.83 (d, 1H, J=8.1 Hz), 7.73 (dd, 1H, J=7.2, 1.5 Hz) 7.66 (t, 1H, J=7.8Hz), 6.96 (d, 1H, J=8.4 Hz), 6.14 (s, 2H), 4.44 (s, 2H); ¹³C NMR(DMSO-d₆) δ 150.6, 147.0, 145.2, 135.6, 130.6, 129.3, 129.1, 127.7,127.5, 125.0, 1.23.6, 117.2, 116.1, 107.5, 101.6, and 26.6. Anal. Calcd.for C₁₇H₁₁NO₂.0.12CH₂Cl₂: C, 75.75; H, 4.17; N, 5.16. Found: C, 75.75 H,4.03, N, 4.83.

Method B:

A solution of 5-[(5-bromo-1,3-benzodioxol-4-yl)methyl]-isoquinoline(12.6 g, 36.8 mmol) and 2,2′-azobisisobutylronitrile (5.92 g, 36.0 mmol)in benzene (1500 mL) was cooled to −78° C., degassed/purged four timeswith nitrogen and then heated to 80° C. under argon. A solution oftributyltin hydride (39.9 g, 137 mmol) in 30 mL of degassed benzene wasadded dropwise over a period of three hours. Acetic acid (12.6 g, 210mmol) was added in one portion before the addition of tin hydride. Thereaction mixture was stirred at 80° C. under argon for 16 hours. Excesstriethylamine was added to neutralize the residual acetic acidcomponent. The solvent was removed under reduced pressure. Methylenechloride (250 mL) was added to dissolve the semi-solid. It was followedby the addition of hexanes to a point just before the mixture becamecloudy. This solution was poured over a short bed of silica gel and thetri-n-butyltin acetate was removed by washing with hexanes until it isno longer, detected by TLC. The product was then eluted out withmixtures of hexanes and ethyl acetate to give the desired title compound(6.1 g, 23.4 mmol, 63.5% yield) which was identical to the productprepared by Method A.

EXAMPLE 8(±)-8,9-Methylenedioxy-2,3,7,11b-tetrahydro-1H-napth[1,2,3-de]isoguinoline

Method A:

To a solution of 12H-benzo[d,e][1,3]benzodioxol[4,5-h]isoquinoline (6.08g, 0.33 mmol) in THF (43 mL) was added 2N HCl (1.7 mL, 3.4 mmol) and anorange precipitate formed. Sodium cyanoborohydride (0.274 g, 4.4 mmol)was added in one portion. The resulting suspension was stirred at roomtemperature for two hours. HCl (2N, 10 mL) was added and stirringcontinued for 5 minutes. Saturated NaHCO₃ solution was added (pH˜7-8).The resulting mixture was extracted with EtOAc, dried over Na₂SO₄ andthe solvent was removed under reduced pressure. Chromatography (SiO₂Type-H, 5% MeOH in CH₂Cl₂) of the residue yielded the title compound asa yellow gum (0.066 g, 0.25 mmol, 75% yield);

¹H NMR (CDCl₃) δ 7.15 (m, 2H), 6.97 (d, 1H, J=6.9 Hz), 6.83 (br, s, 1H),6.68 (d, 1H, J=8.1 Hz), 6.59 (d, 1H, J=8.1 Hz), 6.01 (d, 1H, J=1.4 Hz),5.91 (d; 1H, J=1.4 Hz), 4.40-4.00 (m, 5H), 3.55 (dd, H, J=17.7, 3.0 Hz),3.10 (t, 1H, J=12.0 Hz); ¹³C NMR (CDCl₃) δ 146.1, 144.8, 136.0, 132.2,130.4, 128.6, 127.1, 127.0, 124.5, 118.5, 116.2, 106.2, 101.2, 45.8,35.1, 34.3, and 28.9. Anal. Calcd. for C₁₇H₁₅NO₂.0.52HCN.1.8H₂O: C,67.49; H, 6.18; N, 6.83. Found: C, 67.45 H, 5.96, N, 6.75.

Method B:

12H-Benzo[d,e][1,3]benzodioxol[4,5-h]isoquinoline (11.26 g) wasdissolved into 500 mL of glacial acetic acid in a suitable glass linerthat will fit into a 1-L Parr “bomb reactor”. To this dark ambersolution was added 480 mg PtO₂ and a magnetic stirring bar. Usual purgecycles were repeated three times at −78° C. Finally hydrogen gas wascharged into the steel bomb at 140 PSI while the content was still at−78° C. The reactor was allowed to warm to room temperature over aperiod of 2 hours while the internal pressure increased to 195 PSI. Gasabsorption was faster after about 4 hours at room temperature. After 24hours, the internal pressure returned to 165 PSI indicating roughlystoichlometric uptake of hydrogen gas. The black suspension was removedafter the pressure was relieved, it was filtered over silica gel, rinsedwith acetic acid and concentrated under reduced pressure to give about19 gm of gummy substance. The crude product was neutralized with sodiumbicarbonate solution followed by extraction with methylene chloride toyield 11.6 gm of the title compound whose ¹H NMR was indistinguishablefrom the purified material prepared above by the Method A.

EXAMPLE 9 5-Bromo-1,3-benzodioxol-4-yl)-(5-isoguinolinyl)methanone

To a solution of secondary alcoholα-(5-bromo-1,3-benzodioxol-4-yl)-5-isoquinolinemethanol (1.39 mmol) inbenzene (200 mL), manganese dioxide (28.0 mmol) was added and thereaction mixture was stirred vigorously overnight at room temperature.Excess MnO₂ was filtered through Celite, washed with EtOAc (2×) and thefiltrate washings were combined and concentrated to give a pure yellowsolid, product (quantitative yield). The product was recrystallized withEtOAc/Hexane to afford the title compound: mp 193-195° C.;

¹H NMR (CDCl₃) δ 9.33 (s, 1H), 8.86 (d, 1H, J=6.09 Hz), 8.71 (d, 1H,J=6.06 Hz), 8.19 (d, 1H, J=8.16 Hz), 7.97 (d, 1H, J=38 Hz), 7.61 (t, 1H,J=8.13 Hz), 7.10 (d, 1H, J=8.28 Hz, 6.81 (d, 1H, J=8.28 Hz), 5.97 (s,2H); ¹³C NMR (CDCl₃) δ 192.8, 153.0, 147.7, 146.2, 136.6, 134.3, 133.9,131.9, 129.1, 126.2, 126.1, 123.4, 118.8, 110.9, 110.7, 102.7. Anal.Calcd. for C₁₇H₁₀BrNO₃: C, 57.33; H, 2.83; Br, 22.43; N, 3.93 Found: C,57.3; H, 2.76; Br, 22.73; N, 3.82.

EXAMPLE 10 12H-Benzo[d,e][1,3benzodioxol4,5-h]isoquinolin-12-one

To a solution of ketone(5-bromo-1,3-benzodioxol-4-yl)-(5-isoquinolinyl)methanone (0.56 mmol) inbenzene (12 mL), tributyltin hydride (0.06 mmol) and2,2′-azobisisobutylronitrile (0.035 mmol) were added and the resultingmixture was refluxed for 40 hours under nitrogen. The solvent wasremoved in vacuo and the residue was dissolved in acetonitrile andwashed with hexane(3×). The extract was concentrated in vacuo andsubjected to column chromatography (EtOAc/Hexane). The product wasisolated to afford a yellow fluorescent solid. The product wasrecrystallized (10% yield) with EtOAc/Hexane to afford the titlecompound: MS (ESI) m/e 275.

¹H NMR (DMSO-d₆) δ 9.59 (s, 1H), 9.47 (s, 1H), 8.69 (dd, 1H, J=7.50, 1.2Hz), 8.61 (dd, 1H, J=8.10, 1.20 Hz), 8.26 (d, 1H, J=8.40). 8.02 (t, 1H,J=7.50 Hz, 7.43 (d, 1H, J=8.40 Hz), 6.33 (s, 2H).

EXAMPLE 11(±)-8,9-Dihydrox-2,3,7,11b-tetrahydro-1H-napth[1,2,3-de]isoquinoline

BBr₃ (25.0 mL of 1M in CH₂Cl₂, 25.0 mmol) was added to a cooled solution(−78° C.) of methylenedioxy dinapsoline as prepared in Example 8 (1.4 g,5.3 mmol) in CH₂Cl₂; The mixture was stirred at −78° C. under nitrogenfor three hours and then at room temperature overnight. After themixture was cooled to −78° C., methanol (50 mL) was added dropwise andthe solvent was removed by reduced pressure. The residue was dissolvedin methanol (100 mL) and the solution was refluxed under nitrogen for 2hours. After removal of solvent, chromatography (SiO₂, 10% MeOH inCH₂Cl₂) of the residue yielded the title compound as a dark brown solid(1.65 g, 4.94 mmol, 93% yield). MS (ESI) m/z 254 (MH⁺);

¹H NMR (DMSO-d₆) δ 9.50 (br, s, 2H), 9.28 (s, 1H), 8.54 (s, 1H), 7.32(d, 1H, J=8.3 Hz), 7.23 (t, 1H, J=8.3 Hz), 7.12 (d, 1H, J=8.5 Hz), 6.70(d, 1 H, J=9.3 Hz), 6.54 (d, 1H, J=6.7 Hz), 4.37 (s, 2H), 4.30-4.23 (m,2H), 3.97 (m, 1H), 3.45-3.31 (m, 2H); ¹³C NMR (DMSO-d₆) δ 143.8, 142.0,136.9, 132.1, 127.6, 127.0, 126.6, 124.1, 123.7, 114.0, 112.7, 48.6,44.0, 32.9, and 28.5. Anal. Calcd. for C₁₆H₁₅NO₂.1.28HBr.0.59H₂O: C,52.34; H, 4.79; N, 3.82. Found: C, 52.29; H, 4.92, N, 4.14.

EXAMPLE 12 12H-Benzo[d,e][1,3]benzodioxol[4,5-h]isoquinoline

A sample of(±)-8,9-methylenedioxy-2,3,7,11b-tetrahydro-1H-napth[1,2,3-de]isoquinoline(651 mg) was dissolved into 250 mL of reagent grade xylenes. To thissolution was added 40 mg of 5% Pd on charcoal catalyst and thesuspension was warmed to reflux under nitrogen atmosphere. A smallaliquot was removed after 24 hr and was analyzed by LC/MC to showcomplete oxidation. The catalyst was removed by filtration through ashort bed of silica gel (Type-H) and the orange color filtrate wasconcentrated under reduced pressure to give 640 mg of dark orangecrystals. The NMR of this sample of the title compound wasindistinguishable from a sample prepared in Example 7.

EXAMPLE 13(±)-N-Methyl-8,9-Dihydrox-2,3,7,11b-tetrahydro-1H-napth[1,2,3-de]isoquinoline

Step A. N-Methyl-12H-benzo[d,e][1,3]benzadioxol[4,5-h]isoquinoline

To a solution of 12H-benzo[d,e][1,3]benzodioxol[4,5-h]-isoquinoline(0.38 mmol) in warm dichloroethane (4 mL), methyl iodide (12.8 mmol) wasadded and after a few minutes a yellow suspension was observed. Thereaction was warmed to 40° C. with stirring for 20 minutes. After allthe starting material was gone, nitrogen was blown into the system toremove both the solvent and excess MeI and then dried further under highvacuum. The resulting yellow residue was resuspended in THF and thensodium triacetoxyborohydride (0.4 g) and sodium cyanoborohydride (0.12g) were added. After a few minutes the suspension turns orange andstirring was continued for 20 minutes. Saturated ammonium chloride andhydrochloric acid (2N) were added to the suspension to form two layers.Then sodium cyanoborohydride (0.12 g) was added and stirred for 30minutes. The layers were separated and the organic layer was evaporatedand dried under vacuo. Partial isolation and purification of product wasachieved by recrystallization to give the title compound (0.047 g) andthe mother liquor was purified by column filtration to afford moreproduct (0.04 g, 82% yield):

¹H NMR (DMSO-d₆) δ 7.39 (d, 1H, J=7.35 Hz), 7.28 (t, 1H, J=7.47 Hz),7.13 (d, 1H, J=7.29 Hz), 6.86 (d, 1H, J=8.04 Hz), 6.72 (d, 1H, J=7.95Hz), 6.09 (s, 1 Hz), 6.02 (s, 1H), 4.60-4.25 (m, 3H), 4.20-4.03 (m, 2H),3.75-3.68 (m, 1H), 3.60-3.40 (m, 1H), 3.02 (s, 3H); LCMS Calcd. forC₁₈H₁₇NO₂ (M⁺): 279.13. Found: (MH⁺) 280.13.

Step B.(±)-N-Methyl-8,9-Dihydroxy-2,3,7,11b-tetrahydro-1H-napth[1,2,3-de]isoquinoline

To a solution of the compound of Step A (0.16 mmol) in dichloromethane(4 mL) cooled to −78° C., boron tribromide (1M in dichloromethane, 0.77mmol) was added. The reaction solution was stirred at −78° C. for twohours and warned to room temperature overnight. The solution was cooledto −78° C. and dry methanol was added to quenched the reaction. Afterstirring for to minutes, the solvent was removed and dry methanol wasadded. The process was repeated three times. Purification was performedby recrystallization with MeOH/CH₂CH₂ to obtain the title compound(0.035 g):

¹H NMR (MeOD-d₃) δ 7.37 (d, 1H, J=7.26 Hz), 7.29 (t, 1H, J=7.35 Hz),7.11 (d, 1H, J=7.32 Hz), 6.72 (d, 1H, J=8.19 Hz), 6.59 (d, 1H, J=8.49),4.7-4.39 (m, 3H), 4.20-4.05 (m, 1H) 3.70-3.40 (m, 2H), 3.20 (s, 3H);LCMS Calcd. for C₁₇H₁₇NO₂ (M⁺): 267.13. Found: (MH⁺) 268.16.

What is claimed is:
 1. A process for preparing a compound of the formula

wherein R¹ and R² each are hydrogen; A is CH₂, CHOH or C═O; R ishydrogen or C₁₋₄alkyl; and R⁴, R⁵ and R⁶ each are independentlyhydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, hydroxy or halogen, comprising thesteps of (a) reducing a compound of the formula

wherein R¹ and R² each are a hydroxy-protecting group; or R¹ and R² maybe joined together to form —(CH₂)_(n)— in which n is 1 to 3 and R⁴, R⁵and R⁶ and A are as defined above; with a reducing agent and (b)deprotecting the resulting reduced product to produce the compound ofFormula IX wherein R¹ and R² are hydrogen and (c) optionally, alkylatingthe product of step (a) or (b) to produce a compound of Formula IXwherein R is C₁₋₄alkyl.
 2. The process of claim 1 wherein A is CH₂. 3.The process of claim 2 wherein R¹ and R² are joined together to form—(CH₂)_(n)— in which n is
 1. 4. The process of claim 3 wherein and R⁴,R⁵ and R⁶ are hydrogen.
 5. The process of claim 1 wherein said reducingagent is sodium cyanoborohydride.
 6. The process of claim 1 wherein saiddeprotecting agent is boron tribromide.
 7. A compound of the formula

wherein R¹ and R² each are hydrogen or a hydroxy-protecting group; or R¹and R₂ may be joined together to form —(CH₂)_(n)—, n is 1 to 3; A isCHOR¹ or C═O; R is hydrogen or C₁₋₄alkyl; and R⁴, R⁵ and R⁶ each areindependently hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, hydroxy or halogen. 8.The compound of claim 7 wherein R¹ and R² are hydrogen and A is CHOR¹ inwhich R¹ is hydrogen.
 9. The compound of claim 7 wherein R¹ and R² arehydrogen and A is C═O.
 10. The compound of claim 8 wherein R⁴, R⁵ and R⁶are hydrogen.
 11. The compound of claim 10 wherein R is hydrogen.
 12. Apharmaceutical composition for the treatment of dopamine-relateddisorders comprising a therapeutically effective amount of a compound asdefined in claim 7 in association with a pharmaceutically acceptablecarrier or diluent.
 13. A method for the treatment of dopamine-relateddisorders in a mammal in need thereof, which comprises administering tosaid mammal a therapeutically effective amount of a compound as definedin claim 7.